Honing the Phenotype

Delineation of the Fear of Harm (FOH) phenotype resulted from the same type of dimensional analysis that defined the Core phenotype (Click here to read about dimensional analysis, click here to read about the Core phenotype) However, this time, instead of gathering symptom profiles from all children who were at risk for, or had a diagnosis of, bipolar disorder, investigators gathered data from children who had a high degree of the fear-of-harm trait.

The fear-of-harm trait is highly heritable and  genetically expressed. (Click here to read How Was the Fear-of-Harm Trait Defined).  This increased the likelihood that the profile of dimensions that associate with it would also reflect a biological construct and may be better able to suggest a neuroanatomical model than could a dimensional profile that is not associated with a heritable trait. (Click here to view the 6 dimensions that define the FOH phenotype)

Arriving at a Hypothesis

The dimensional profile that emerged led investigators to a neuroanatomical hypothesis. Of the six most relevant dimensions, one in particular caught the attention of the investigators. The dimension is called PPSO, (parasomnias/psychosis/sweet cravings/obsessions); it suggested to investigators that children who have a high level of fear-of-harm are characterized by disturbances in appetite, as well as sleep/arousal systems.

In juvenile bipolar disorder, disturbances in the quality of both sleep and wakefulness are prominent. Preliminary data from parental reports of children with bipolar disorder indicate that a diverse set of sleep problems, particularly sleep-onset delay and sleep fragmentation and morning sleep inertia, are severe and more frequent relative to children with other psychiatric disorders or primary sleep disorders, in a community sample of children.

Disturbances in brain areas that regulate these functions would likely result in those difficulties. This pointed the investigators towards the hypothalamic preoptic area of the brain. Much exploration of the known-information about this brain area, the transmitters particular to it and the networks it both sends out and links to, enabled investigators to form a complex hypothesis in which the broad range of symptoms experienced by the population of children they studied is likely to be attributed to dysregulation of the orexigenic-neuropeptide pathway.  This evolutionarily ancient pathway is critical to the proper functioning of homeostasis.

Homeostasis is the state of biological balance that needs to be maintained in order for us to function as complex organisms as well as to survive harmoniously within the environment in which we evolved. It expresses itself in basic behaviors such as arousal (sleep/activity), metabolism (eating and expending energy), modulation to our environment (thermoregulation, ultradian, circadian and seasonal rhythms), and reproduction (sexual arousal). The disruption of this pathway can result in a very broad range of downstream symptoms.

From this unified framework, symptoms that range from sweating to carbohydrate craving to sleeplessness and behaviors that range from anger to depression to anxiety can all be understood to be downstream results of this upstream problem.

The neuroanatomical insights gained through the research have pointed investigators to potential treatments to correct the dysregulation.  It would appear so far that children characterized by the fear-of-harm trait respond very favorably to the treatment.  Further studies will provide more evidence that will bolster the treatment observations as well as provide validity for the phenotype.

The list of Six Dimensions of Behavior that Define the FOH phenotype will provide a view of the symptoms most characteristic of  the phenotype.  To read the published article that more thoroughly discusses the course and severity of the illness, the severity of mania and depression associated with the trait, and the beginning of the neuroanatomical hypothesis, click Fear of harm, a possible phenotype of pediatric bipolar disorder: A dimensional approach to diagnosis for genotyping psychiatric syndromes.

Please note: Investigators are currently writing the complete hypothesis paper which will be posted as soon as it is available.